Effect of Gastric Fluid Volume on the In Vitro Dissolution and In Vivo Absorption of BCS Class II Drugs: a Case Study with Nifedipine.

Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large inter-patient variability in nifedipine absorption results in variable exposure among different patients. We conducted in vitro dissolution studies to compare nifedipine dissolution from immediate release (IR) capsules with different volumes of dissolution media. Results from dissolution studies were used to design a crossover study in healthy volunteers to evaluate the effect of coadministered water volume with nifedipine 10 mg IR capsules on nifedipine pharmacokinetics, especially absorption (C max, t max, and AUC0-6). Dissolution studies demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution from 10 mg IR cosolvent capsules (73 vs. 17% in 200 and 100 mL simulated gastric fluid, respectively, at 30 min). The pharmacokinetic crossover study in healthy volunteers (N = 6) did not show a significant effect of the water volume administered with the capsule (50 vs. 250 mL) on C max, t max, or AUC0-6 of orally administered nifedipine IR capsules (10 mg). However, administration of large water volumes resulted in lower variability in nifedipine C max (47 vs. 70% for 250 and 50 mL, respectively). Administration of large water volumes with nifedipine 10 mg IR cosolvent capsules may reduce inter-individual variability in plasma exposure. Evaluation of similar effects in other BCS Class II drugs is recommended.

Pharmacokinetics of ertapenem in critically ill patients receiving continuous venovenous hemodialysis or hemodiafiltration.

This study characterizes the pharmacokinetics of ertapenem, a carbapenem antibiotic, in critically ill adult subjects receiving continuous renal replacement therapy (CRRT). Eight critically ill patients with suspected/known Gram-negative infections receiving continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF) and ertapenem were enrolled. One gram of ertapenem was infused over 30 min. Predialyzer blood samples were drawn with the first dose of ertapenem from the hemodialysis tubing at time zero, 30 min, and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. Effluent was collected at the same time points. Ertapenem total serum, unbound serum, and effluent concentrations from all eight subjects were used simultaneously to perform a population compartmental pharmacokinetic modeling procedure using NONMEM. Monte Carlo simulations were performed to evaluate the ability of several ertapenem dosing regimens (500 mg once daily, 750 mg once daily, 500 mg twice daily, and 1,000 mg once daily) to obtain effective unbound serum concentrations above 0.5, 1, and 2 µg/ml. For our simulated patients, all regimens produced unbound ertapenem concentrations above 2 µg/ml for 40% of the dosing interval for at least 96% of simulated patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00877370.).

Suitability of digoxin as a P-glycoprotein probe: implications of other transporters on sensitivity and specificity.

The study of transporter-mediated drug-drug interactions (DDI) requires use of appropriate probes to reflect transporter function. Digoxin is often used as a probe in DDI studies involving P-glycoprotein (P-gp) and is recommended by FDA for this purpose, despite several lingering questions regarding suitability of digoxin as P-gp probe. This review aims to critically evaluate use of digoxin as a probe for P-gp-mediated clinical DDI studies, with focus on sensitivity and specificity of digoxin for P-gp. Although previous reviews have evaluated digoxin transport by P-gp, the purpose of the current review is to critically evaluate such literature in light of newly evolving literature suggesting digoxin transport by non-P-gp transporters.